Among compounds with tyrosinase inhibitory activity, natural products, such as arbutin and kojic acid, are often used as whitening agents in the cosmetic and other fields (e.g., Journal of the Pharmaceutical Society of Japan, 112 (4), pp. 276-282, 1992; Journal of the Pharmaceutical Society of Japan, 115 (8), pp. 626-632, 1995; BIO INDUSTRY, 11 (4), 206, 1994; and Biosci. Biotech. Biochem., 61, 11, pp. 1926-1928, 1997). However, when used as external preparations for the skin, such as cosmetics, these compounds have the drawback in that they have high hydrophilicity and thus have poor skin absorption properties. Therefore, development of arbutin derivatives or other compounds with higher hydrophobicity have been desired. An arbutin derivative in which the phenol moiety has been esterified is known as a bleaching agent (Japanese Unexamined Patent Publication No. 1999-71225). Further, a compound obtained by converting the 6-position of arbutin into a hydroxy ester is known as a bleaching cosmetic preparation (Japanese Unexamined Patent Publication No. 1993-194181). Furthermore, a compound obtained by a transesterification reaction of arbutin and vinyl cinnamate using lipase to selectively esterify the 6-position of arbutin has been reported (Bioscience Biotechnology and Biochemistry, 61, 11, pp. 1926-1928, 1997). However, tyrosinase inhibitory activity of arbutin derivatives and skin-whitening effects based on the activity have not been established, and no arbutin derivatives with satisfactory effects have yet been obtained.
Undecylenic acid is a C11 unsaturated fatty acid contained in the human skin, and plays an important role as a skin cleansing agent. Commercially, it is produced by pyrolysis of castor oil. Undecylenic acid and salts and derivatives thereof are known to have antifungal activity, and reportedly can be used as skin cleansing preparations (Japanese Unexamined Patent Publication No. 2002-114669). Recently, trehalose esters have been developed as cosmetic materials (Japanese Unexamined Patent Publications No. 2001-278752 and No. 1993-137994). However, no tyrosinase inhibitory activity of undecylenic acid, salts thereof and ester derivatives thereof has been reported.
Meanwhile, gray hair, an aging phenomenon, is known to be caused by a lack of melanin pigments being transferred to keratinocytes. Therefore, researchers have searched mainly for tyrosinase activity promoting components and melanogenesis promoting components in order to develop a hair graying inhibitor. Specifically, they have attempted to find hair graying inhibitory activity in extracts of natural products and various other substances, and to use various compounds as active ingredients. For example, Japanese Unexamined Patent Publication No. 1995-316048 proposed that ω-alkoxycarbonylalkylammonium, salts thereof, ω-alkoxycarbonylalkyltrialkylammonium and salts thereof are effective as melanogenesis promoters. Also proposed were adenosine derivatives (Japanese Unexamined Patent Publication No. 1994-305940) and dihydrolupeol derivatives (Japanese Unexamined Patent Publication No. 2002-3381). However, the safety of these chemical substances is not assured. Japanese Unexamined Patent Publication No. 1993-78222 proposed a hair graying inhibitor comprising an aqueous or ethanolic extract of Japanese coptis as an active ingredient. Japanese Unexamined Patent Publication No. 1995-285874 proposed a melanogenesis promoter comprising an essence of shellfish, such as cockles, green mussels, oysters or the like. Japanese Unexamined Patent Publication No. 1999-124318 proposed a hair graying inhibitor comprising, as an active ingredient, at least one member selected from Equisetum arvense L., Lonicera japonica Thunb., Plectranthus japonicus, Vitis vinifera L., Luffa cylindrica Roem., Sambucus nigra, Rucus aculeatus L., Zizyphus jujuba, and extracts thereof. Japanese Unexamined Patent Publication No. 1995-316026 proposed a hair preparation comprising at least one melanogenesis promoting component selected from culture solutions and cell extracts of basidiomycetes of the families Tricholomataceae, Hydnaceae, Polyporaceae, Fistulinaceae, Mucronoporaceae, Helvellaceae, Strophariaceae and Agaricaceae. Japanese Unexamined Patent Publication No. 1999-189541 proposed that Piper methysticum and extracts thereof exhibit a melanogenesis promoting effect. Further, melanogenesis promoting effects have been confirmed in extracts of seaweeds of the genus Spyridia and Dictyota dichotoma (Japanese Unexamined Patent Publication No. 1998-330218), extracts of Panax ginseng C. A. Meyer, Panax notoginseng, Salvia miltiorrhiza, Yucca elephantipes, Eriobotrya japonica Lindley, Lonicera japonica and Sarsaparilla (Japanese Unexamined Patent Publication No. 2001-288098), and Ficus carica, Morus alba and extracts thereof (Japanese Unexamined Patent Publication No. 2002-47130). However, the production of plant or animal extracts has limitations in availability of the raw materials, and the extracts have drawbacks in that the raw material concentration is inconsistent, resulting in unreliable performance. Therefore, the development of a synthetic compound with sufficient tyrosinase activity promoting effect and melanogenesis promoting effect has been desired.
In the food industry, enzymatic esterification reactions applicable to the production of ester compounds as mentioned above have already been put into practice using hydrophobic alcohols and fatty acids as raw materials (Bioindustry, 19, pp. 62-71 (2002)). However, when a hydrophilic compound that is sparingly soluble in hydrophobic solvents is used as a raw material, the reaction results in a low yield and is not readily applicable to practical production processes. Japanese Unexamined Patent Publication No. 1996-245680 reported a process for producing a sucrose ester in octane, hexane or like organic solvent using an enzyme that is soluble in organic solvents. However, since sucrose is sparingly soluble in such solvents, the process does not produce a high yield. Carbohydrates and purine nucleosides are, however, highly soluble in DMSO, DMF, and like solvents. For example, sucrose dissolves in DMSO to a concentration of about 40% (Advance of Carbohydrate Chemistry and Biochemistry, 27, pp. 85-125 (1972)). Purine nucleosides, such as guanosine, dissolve in DMF containing 50% or more of DMSO. However, it has been assumed that use of aprotic organic solvents, such as DMF and DMSO, is generally liable to inactivate hydrolases, making it difficult to perform reactions (Japanese Unexamined Patent Publications No. 1997-271387 and No. 1996-9987). Therefore, an enzyme that shows high activity even in solvents in which hydrophilic compounds are highly soluble is sought. Hitherto, proteases derived from bacteria of the genera Bacillus and Streptomyces have been found as enzymes that show high activity in DMF or like solvent (Journal of American Chemical Society, 110, pp. 584-589 (1988)). However, no enzymes have been found so far which retain high activities in solvents capable of dissolving saccharides and nucleosides.